Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response

Bonnet, Marie-Elise; Erbacher, Patrick; Bolcato-Bellemin, Anne-Laure

doi:10.1007/s11095-008-9693-1

Cited by 137 publications

(105 citation statements)

References 72 publications

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“…For gene knockdown or gene overexpression, delivery of siRNA and DNA into mice was performed using retro-orbital injection of the mixture with jet PEI (PolyPlus) or Exgen (Fermentas) per the manufacturer's instructions, respectively 3,23,24,58 . Control DNA (vector only) and siRNA with irrelevant sequence were used as controls; these delivery methods have been shown not to elevate the serum levels of major pro-inflammatory cytokines (for example, TNF-a, IL-6 and so on) 59 . Gene knockdown or overexpression in the lung (2 days later) was confirmed by measuring mRNA and/or protein levels using qRT-PCR and IB, respectively.…”

Section: Methodsmentioning

confidence: 99%

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

et al. 2013

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Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. Most past work on vascular barrier function has focused on soluble regulators, such as tumour-necrosis factor-a. Here we show that lung vascular permeability is controlled mechanically by changes in extracellular matrix structure. Our studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. Importantly, endotoxin-induced increases of vascular permeability are accompanied by concomitant increases in extracellular matrix rigidity and lysyl oxidase activity, which can be prevented by inhibiting lysyl oxidase activity. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability.

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Section: Methodsmentioning

confidence: 99%

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

et al. 2013

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“…Therefore, all components of this type of system need to be safe, including the delivery vehicle, the transgene expressed, and the DNA vector itself. Although many delivery formulations are possible, we chose an in vivo transfection agent that has an excellent safety profile (i.e., no immunostimulation) (31) and is in phase I/II clinical trials (32)(33)(34). We chose the transgene SEAP because it is of human origin, so it should not cause an immunogenic reaction (17), and already has shown promise in the clinic (18).…”

Section: Discussionmentioning

confidence: 99%

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Ronald

Chuang

Dragulescu-Andrasi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumorspecific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 ± 0.084. Lung tumor burden additionally correlated (r 2 = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer-screening tool for the general population.cancer | minicircles | tumor-specific promoter | reporter gene | blood test

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“…Various promising nanoparticles (NPs) strategies that have been successful in depicting in vitro gene silencing and tumor reduction efficacy in animal models, safety in non-human primates and in few cases, have undergone clinical trial testing include, (A) Lipid based NPs: liposomes [16], lipoplexes [17,18], stable nucleic acid lipid nanoparticles (SNALP) [19,20] & lipidoid [21], polycation liposomes [22,23], (B) Polymeric NPs: both natural and synthetic, includes cyclodextrin [24], chitosan [25], PLGA [26], polymeric micelles [27], PEI [28] & dendrimers [29], (C) Inorganic NPs: calcium phosphate CaP [30], (D) Carbon-based materials, carbon nanotubes (SWNTs, MWNTs) [31,32], (E) Metal nanoparticles -Gold (Au) [33], Quantum dots (QDs) [34], silicon-based nanoparticles (MSNPs) [35] & super paramagnetic iron oxide nanoparticles (SPIONs) [36] etc. In addition to this, atelocollagen-based delivery strategy also proved to be successful in few cases [37,38].…”

Section: Nanotechnology-based Delivery Strategiesmentioning

confidence: 99%

RNAi-based Cancer Therapeutics: Are we there yet?

Saxena¹

2014

J Pharmacovigil

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RNAi-based therapeutics remains one of the most promising strategies for the effective cancer treatment due to its high target-specificity, precise mechanism of action, greater potency and reduced side effects. Although, tremendous progress and advances have been made in the past few years to develop nanotechnology-based efficient non-viral delivery systems, there are still many hurdles and challenges that must be conquered to achieve the target of clinically relevant formulation in terms of safety, specificity and efficacy.

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Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response

Abstract: Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.

Cited by 137 publications

References 72 publications

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

RNAi-based Cancer Therapeutics: Are we there yet?

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